N-substituted indole-3glyoxylamides having anti-asthmatic, antiallergic and immunosuppressant/immuno-modulating action

ABSTRACT

The invention relates to novel N-substituted indole-3-glyoxylamides, to processes for their preparation and to their pharmaceutical use. The compounds have antiasthmatic, antiallergic and immunosuppressant/immunomodulating actions.

DESCRIPTION

[0001] Indole-3-glyoxylamides have various uses as pharmaco-dynamicallyactive compounds and as synthesis components in the pharmaceuticalchemistry.

[0002] The Patent Application NL 6502481 describes compounds which havean antiinflammatory and antipyretic profile of action and analgesicactivity.

[0003] The British Patent GB 1 028 812 mentions derivatives ofindolyl-3-glyoxylic acid and its amides as compounds having analgesic,anticonvulsant and β-adrenergic activity.

[0004] G. Domschke et al. (Ber. 94, 2353 (1961)) describe3-indolylglyoxylamides which are not characterized pharmacologically.

[0005] E. Walton et al. in J. Med. Chem. 11, 1252 (1968) report onindolyl-3-glyoxylic acid derivatives which have an inhibitory activityon glycerophosphate dehydrogenase and lactate dehydrogenase.

[0006] Euoropean Patent Specification EP 0 675 110 A1 describes1H-indole-3-glyoxylamides which are profiled as sPLA2 inhibitors and areused in the treatment of septic shock, in pancreatitis, and in thetreatment of allergic rhinitis and rheumatoid arthritis.

[0007] The aim of the present invention is to make available novelcompounds from the indolyl-3-glyoxylic acid series, which haveantiasthmatic and immunomodulating action.

[0008] The chemical processes for the preparation of these compounds andpharmaceutical processes for the conversion of the novel compounds intomedicaments and their preparation forms are furthermore described.

[0009] The subject matter of the invention comprises compounds of thegeneral formula I,

[0010] where the radicals R, R₁, R₂, R₃, R₄ and Z have the followingmeaning:

[0011] R=hydrogen, (C₁-C₆)-alkyl, where the alkyl group can be mono- orpolysubstituted by the phenyl ring. This phenyl ring, for its part, canbe mono- or polysubstituted by halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with(C₁-C₆)-alkanols, trifluoromethyl groups, hydroxyl groups, methoxygroups, ethoxy groups, benzyloxy groups and by a benzyl group which ismono- or polysubstituted in the phenyl moiety by (C₁-C₆)-alkyl groupshalogen atoms or trifluoromethyl groups.

[0012] R₁ can be a phenyl ring which is mono- or poly-substituted by(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxyl, benzyloxy, nitro, amino,(C₁-C₆)-alkylamino, (C₁-C₆)-alkoxy-carbonylamino and by a carboxyl groupor a carboxyl group esterified by (C₁-C₆)-alkanols, or is a pyridinstructure of the formula II

[0013] where the pyridin structure is alternatively bonded to the ringcarbon atoms 2, 3 and 4 and can be substituted by the substitutents R₅and R₆. The radicals R₅ and R₆ can be identical or different and havethe meaning (C₁-C₆)-alkyl, and also the meaning (C₃-C₇)-cycloalkyl,(C₁-C₆)-alkoxy, nitro, amino, hydroxyl, halogen and trifluoromethyl andare furthermore the ethoxy-carbonylamino radical and the groupcarboxy-alkyloxy in which the alkyl group can have 1-4 C atoms.

[0014] R₁ can furthermore be a 2- or 4-pyrimidinyl-heterocycle or apyridylmethyl radical in which CH₂ can be in the 2-, 3-, 4-positionwhere the 2-pyrimidinyl ring can be mono- or polysubstituted by themethyl group, furthermore are [sic] the 2-, 3- and 4-quinolyl structuresubstituted by (C₁-C₆)-alkyl, halogen, the nitro group, the amino groupand the (C₁-C₆)-alkylamino radical, or are [sic] a 2-, 3- and4-quinolylmethyl group, where the ring carbons of the pyridylmethyl andquinolylmethyl radical can be substituted by (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, nitro, amino and (C₁-C₆)-alkoxy-carbonylamino.

[0015] R₁ for the case where R is hydrogen or the benzyl group, canfurthermore be the acid radical of a natural or unnatural amino acid,e.g. the α-glycyl, the α-sarcosyl, the α-alanyl, the α-leucyl, theα-isoleucyl, the α-seryl, the α-phenylalanyl, the α-histidyl, theα-prolyl, the α-arginyl, the α-lysyl, the α-asparagyl and the α-glutamylradical, where the amino groups of the respective amino acids can bepresent in unprotected or protected form. Possible protective groups forthe amino function are the carbobenzoxy radical (Z radical) and thetert-butoxycarbonyl radical (BOC radical) and also the acetyl group. Inthe case of the asparagyl and glutamyl radical claimed for R₁, thesecond, nonbonded carboxyl group is present as a free carboxyl group orin the form of an ester with C₁-C₆-alkanols, e.g. as the methyl, ethylor as the tert-butyl ester. R₁ can furthermore be theallylaminocarbonyl-2-methylprop-1-yl group. R and R₁, together with thenitrogen atom to which they are bonded, can furthermore form apiperazine ring of the formula III or a homopiperazine ring if R₁ is anaminoalkylene group in which

[0016] R₇ is an alkyl radical, a phenyl ring which can be mono- orpolysubstituted by (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, halogen, the nitrogroup, the amino function, by (C₁-C₆)-alkylamino, the benzhydryl groupand the bis-p-fluorobenzylhydryl group.

[0017] R₂ can be hydrogen or the (C₁-C₆)-alkyl group, where the alkylgroup can be mono- or polysubstituted by halogen and phenyl which forits part can be mono- or polysubstituted by halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, carboxyl groups, carboxyl groups esterified with(C₁-C₆)-alkanols, trifluoromethyl groups, hydroxyl groups, methoxygroups, ethoxy groups or benzyloxy groups. The (C₁-C₆)-alkyl groupcounting as R₂ can furthermore be substituted by the 2-quinolyl groupand the 2-, 3- and 4-pyridyl structure, which in each case can both bemono- or polysubstituted by halogen, (C₁-C₄)-alkyl groups or(C₁-C₄)-alkoxy groups. R₂ is furthermore the aroyl radical, where thearoyl moiety on which this radical is based is the phenyl ring which canbe mono- or polysubstituted by halogen (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, carboxyl groups, carboxyl groups esterified by(C₁-C₆)-alkanols, trifluoromethyl groups, hydroxyl groups, methoxygroups, ethoxy groups or benzyloxy groups.

[0018] R₃ and R₄ can be identical or different and are hydrogen,hydroxyl, (C₁-C₆)-alkyl, (C₃-C₇)-cyclo-alkyl, (C₁-C₆)-alkanoyl,(C₁-C₁)-alkoxy, halogen and benzyloxy. R₃ and R₄ can furthermore be thenitro group, the amino group, the (C₁-C₄)-mono- or dialkyl-substitutedamino group, and the (C₁-C₃)-alkoxycarbonylamino function or(C₁-C₃)-alkcoxy-carbonylamino-(C₁-C₃)-alkyl function.

[0019] Z is O or S

[0020] The designation alkyl, alkanol, alkoxy or alkylamino group forthe radicals R, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ is normally to beunderstood as meaning “straight-chain” and “branched” alkyl groups,where “straight-chain alkyl groups” can be, for example, radicals suchas methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl and “branchedalkyl groups” designate, for example, radicals such as isopropyl ortert-butyl. “Cycloalkyl” is to be understood as meaning radicals suchas, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl. The designation “halogen” represents fluorine, chlorine,bromine or iodine. The designation “alkoxy group” represents radicalssuch as, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy,isobutoxy or pentoxy.

[0021] The compounds according to the invention can also be present asacid addition salts, for example as salts of mineral acids, such as, forexample, hydrochloric acid, sulfuric acid, phosphoric acid, salts oforganic acids, such as, for example, acetic acid, lactic acid, malonicacid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citricacid, embonic acid, methanesulfonic acid, trifluoroacetic acid andsuccinic acid.

[0022] Both the compounds of the formula I and their salts arebiologically active. The compounds of the formula 1 can be administeredin free form or as salts with a physiologically tolerable acid.Administration can be carried out orally, parenterally, intravenously,transdermally or by inhalation.

[0023] The invention furthermore relates to pharmaceutical preparationscontaining at least one compound of the formula I or its salt withphysiologically tolerable inorganic or organic acids and, ifappropriate, pharmaceutically utilizable excipients and/or diluents orauxiliaries.

[0024] Suitable administration forms are, for example, tablets, coatedtablets, capsules, solutions or ampoules, suppositories, patches, powderpreparations which can be inhaled, suspensions, creams and ointments.

[0025] The compounds according to the invention have a goodantiasthmatic, antiallergic and immuno-suppressant/immunomodulatingaction, for example in transplantations and diseases such as psoriasis,rheumatoid disorders and chronic polyarthritis, in the followingpharmacological models:

[0026] Inhibition of the “Late Phase” Eosinophilia in the BAL 24 HoursAfter Allergen Challenge in Guinea Pigs

[0027] Male guinea pigs (200-250 g, Dunkin Hartley Shoe) were activelysensitized subcutaneously with ovalbumin (10 μg of ovalbumin+1 mg ofAl(OH)₃) and boosted 2 weeks later. One week after boosting withovalbumin, the animals were exposed to an inhalation challenge withovalbumin (0.5% strength solution) for 20-30 seconds. 24 hours later,the animals were killed by means of an overdose of urethane,exsanguinated and a bronchoalveolar lavage (BAL) was carried out using2×5 ml of 0.9% strength physiological saline solution.

[0028] The lavage fluid was collected and centrifuged at 400 g for 10minutes, and the pellets were suspended in 1 ml of 0.9% strengthphysiological saline solution. The eosinophils were countedmicroscopically in a Neubauer chamber after staining by means of BectonDickinson test kit No. 5877. This test kit contains Phloxin B as aselective stain for eosinophils. The eosinophils in the BAL was [sic]counted here for each animal and expressed as eosinophils(millions/animal). For each group the mean value and standard deviationwere determined. The percentage inhibition of eosinophilia for the grouptreated with test substance was calculated according to the followingformula:

(A−B)−(B−C)/(A−C)×100=% inhibition

[0029] in this formula A eosinophils correspond to the untreatedchallenge group, B eosinophils to the treated group and C eosinophils tothe unchallenged control group.

[0030] The animals were treated with a histamine H₁ antagonist(azelastine; 0.01 mg/kg p.o.) 2 hours before allergen challenge to avoiddeath. The administration of the test substances or of the vehicle wascarried out 4 hours after allergen challenge. The percentage inhibitionof eosinophilia in the BAL was calculated on groups of 6-10 animals.TABLE Inhibition of the “late phase”-eosinophilia 24 h after allergenchallenge in guinea pigs Dose % Substance [mg/kg] Administration nInhibition Cyclosporin A 5 i.p. + 4 h 17 50.0 10 i.p. + 4 h 11 47.0 30p.o. + 4 h  10 68.8 According to Ex. 1 5 i.p. + 4 h 10 27.8 10 i.p. + 4h 10 55.4 30 p.o. + 4 h   9 56.1

[0031] Assays for the Determination of Peptidylprolyl Isomerase (PPIase)Activity and Inhibition

[0032] The PPIase activity of the cyclophilins was measuredenzymatically according to Fischer et al. (1984). After isomerization ofthe substrate by the peptidyl prolyl isomerase, this is accessible tochymotrypsin, which cleaves the chromophore p-nitroaniline. For thedetermination of inhibition of the PPIase activity by substance,recombinant human Cyp B was used. The interaction of Cyp B with apotential inhibitor was carried out as follows:

[0033] A certain concentration of purified Cyp B was incubated with 1 μMsubstance for 15 min. The PPIase reaction was started by addition of thesubstrate solution to the reaction mixture which contains HEPES buffer,chymotrypsin and either test or control samples. Under these conditions,first-order kinetics were obtained with a constantK_(observed)=K₀+K_(enz), where K₀ is the spontaneous isomerization andK_(enz) is the rate of isomerization of the PPIase activity. Theextinction values which correspond to the amount of the chromophorecleaved were measured using a Beckman DU 70 spectrophotometer at aconstant reaction temperature of 10° C.

[0034] The observed residual activity in the presence of varioussubstances was compared with the cyclophilins only treated with solvent.The results were given in % residual activity. Cyclosporin A (CsA) wasused as the reference compound. The inhibition of the PPIase activitywas additionally checked by SDS-PAGE.

[0035] Colorimetric Assay (Based on the MTT Test) for theNon-radioactive Quantification of Cell Proliferation and SurvivalAbility

[0036] MTT is used for the quantitative determination of cellproliferation and activation, for example, in the reaction on growthfactors and cytokines such as IL-2 and IL-4 and also for thequantification of the antiproliferative or toxic effects.

[0037] The assay is based on the cleavage of yellow tetrazolium salt MTTto give purple-red formazan crystals by metabolically active cells.

[0038] The cells, cultured in a 96-hole tissue culture plate, areincubated for about 4 h with yellow MTT solution. After this incubationtime, purple-red formazan salt crystals are formed. These salt crystalsare insoluble in aqueous solutions, but can be dissolved by addition ofsolubilizer and by incubation of the plates overnight.

[0039] The dissolved formazan product is quantifiedspectrophotometrically using an ELISA reader. An increase in the numberof living cells results in an increase in the total metabolic activityin the sample. This increase correlates directly with the amount of thepurple-red formazan crystals formed, which are [sic] measured by theabsorption. Inhibition of CD3-induced Inhibition of IL-2 lympho-Inhibition of production proliferation Substance PPIase activity [%] [%]Cono. [μM] [%] 0.1 1 10 0.1 1 10 According to Ex. 1 80 - 100 34 72 95 1839 61 Cyclosporin A 80 - 100 56 82 94  8  7 11

[0040] The processes for the preparation of the compounds according tothe invention are described in the following reaction schemes 1 and 2and in general procedures. All compounds can be prepared as described oranalogously.

[0041] The compounds of the general formula I are obtainable accordingto the following Scheme 1, shown for the synthesis of the compoundExample 1:

[0042] General Procedure for the Preparation of the Compounds of theGeneral Formula I According to Scheme 1:

[0043] 1st Stage

[0044] The indole derivative, which can be unsubstituted or mono- orpolysubstituted on C-2 or in the phenyl structure, is dissolved in aprotic, dipolar aprotic or nonpolar organic solvent, such as, forexample, isopropanol, tetrahydrofuran, dimethyl sulfoxide,dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone, dioxane,toluene or methylene chloride and added dropwise to a suspension of abase in a molar or excess amount prepared in a 3-necked flask under anN₂ atmosphere, such as, for example, sodium hydride, powdered potassiumhydroxide, potassium tert-butoxide, dimethylaminopyridine or sodiumamide in a suitable solvent. The desired alkyl, aralkyl or heteroaralkylhalide, if appropriate with addition of a catalyst, such as, forexample, copper, is then added and the mixture is reacted for some time,for example 30 minutes to 12 hours, and the temperature is kept within arange from 0° C. to 120° C., preferably between 30° C. to [sic] 80° C.,particularly between 50° C. and 65° C. After completion of the reaction,the reaction mixture is added to water, the solution is extracted, forexample, with diethyl ether, dichloromethane, chloroform, methyltert-butyl ether or tetrahydrofuran and the organic phase obtained ineach case is dried using anhydrous sodium sulfate. The organic phase isconcentrated in vacuo, the residue which remains is crystallized bytrituration or the oily residue is purified by recrystallization,distillation or by column or flash chromatography on silica gel oralumina. The eluent used is, for example, a mixture of dichloromethaneand diethyl ether in the ratio 8:2 (vol/vol) or a mixture ofdichloromethane and ethanol in the ratio 9:1 (vol/vol).

[0045] 2nd Stage

[0046] The N-substituted indole obtained by the abovementioned 1st stageprocedure is dissolved under a nitrogen atmosphere in an aprotic ornonpolar organic solvent, such as, for example, diethyl ether, methyltert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylenechloride or chloroform and added to a solution, prepared under anitrogen atmosphere, of a simply molar up to 60 percent excess amount ofoxalyl chloride in an aprotic or nonpolar solvent, such as, for example,in diethyl ether, methyl tert-butylether, tetrahydrofuran, dioxane,toluene, xylene, methylene chloride or chloroform, the temperature beingkept between −5° C. and 20° C. The reaction solution is then heated at atemperature between 10° C. and 130° C., preferably between 20° C. and80° C., particularly between 30° C. and 50° C., for a period of 30minutes up to 5 hours and the solvent is then evaporated. The residue ofthe “indolyl-3-glyoxylic acid chloride” formed in this manner whichremains is dissolved in an aprotic solvent such as, for example,tetrahydrofuran, dioxane, diethyl ether, toluene or alternatively in adipolar aprotic solvent, such as, for example, dimethylformamide,dimethylacetamide or dimethyl sulfoxide, cooled to a temperature between10° C. and −15° C., preferably between −5C and 0° C., and treated in thepresence of an acid scavenger with a solution of the primary orsecondary amine in a diluent.

[0047] Possible diluents are the solvents used above for the dissolutionof the indolyl-3-glyoxylic acid chloride. Acid scavengers used aretriethylamine, pyridin, dimethylaminopyridine, basic ion exchanger,sodium carbonate, potassium carbonate, powdered potassium hydroxide andexcess primary or secondary amine employed for the reaction. Thereaction takes place at a temperature from 0° C. to 120° C., preferablyat 20-80° C., particularly between 40° C. and 60° C. After a reactiontime of 1-3 hours and standing at room temperature for 24 hours, thehydrochloride of the acid scavenger is filtered, the filtrate isconcentrated in vacuo, and the residue is recrystallized from an organicsolvent or purified by column chromatography on silica gel or alumina.The eluent used is, for example, a mixture of dichloromethane andethanol (95:5, vol/vol).

WORKING EXAMPLES

[0048] According to this general procedure for Stages 1 and 2, on whichthe synthesis Scheme 1 is based, the following compounds weresynthesized which are evident from the following survey detailing therespective chemical name. In Table 1 which follows, the structures ofthese compounds and their melting points can be seen from the generalformula I and the substituents R₁-R₄ and Z:

Example 1 N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamide

[0049] 1st Stage

1-(4-Fluorobenzyl)indole

[0050] A solution of 11.72 g (0.1 mol) of indole in 50 ml of dimethylsulfoxide is added to a mixture of 2.64 g of sodium hydride (0.11 mol,mineral oil suspension) in 100 ml of dimethyl sulfoxide. The mixture isheated for 1.5 hours at 60° C., then allowed to cool and 15.9 g (0.11mol) of 4-fluorobenzyl chloride are added dropwise. The solution iswarmed to 60° C., allowed to stand overnight and then poured into 400 mlof water with stirring. The mixture is extracted several times with atotal of 150 ml of methylene chloride, the organic phase is dried usinganhydrous sodium sulfate and filtered, and the filtrate is concentratedin vacuo. The residue is distilled in a high vacuum: 21.0 g (96% oftheory) B.p. (0.5 mm): 140° C.

[0051] 2nd Stage

N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamide

[0052] A solution of 4.75 g (21.1 mmol) of 1-(4-fluoro-benzyl)indole in25 ml of ether is added dropwise at 0° C. and under N₂ to a solution of2.25 ml of oxalyl chloride in 25 ml of ether. The mixture is refluxedfor 2 hours and the solvent is then evaporated. 50 ml of tetrahydrofuranwere [sic] then added to the residue, and the solution is cooled to −5°C. and treated dropwise with a solution of 4.66 g (49.5 mmol) of4-aminopyridine in 200 ml of THF. The mixture is refluxed for 3 hoursand allowed to stand at room temperature overnight. The 4-aminopyridinehydrochloride is filtered off with suction, the precipitate is washedwith THF, the filtrate is concentrated in vacuo and the residue isrecrystallized from ethyl acetate.

[0053] Yield: 7.09 g (90% of theory)

[0054] Melting point: 225-226° C. Elemental analysis: Calc. C 70.77 H4.32 N 11.25 Found C 71.09 H 4.36 N 11.26

Example 2 N-(Pyridin-4-yl)-(1-methylindol-3-yl) glyoxylamide Example 3N-(Pyridin-3-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide Example 4N-(Pyridin-3-yl)-(1-benzylindol-3-yl) glyoxylamide Example 5N-(Pyridin-3-yl)-[1-(2-chlorobenzyl)-indol-3-yl]glyoxylamide Example 6N-(4-Fluorophenyl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide Example 7N-(4-Nitrophenyl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide Example 8N-(2-Chloropyridin-3-yl)-[1-(4-fluoro-benzyl)indol-3-yl]glyoxylamideExample 9 N-(Pyridin-4-yl)-(1-benzylindol-3-yl)-glyoxylamide Example 10N-(Pyridin-4-yl)-[1-(3-pyridylmethyl)-indol-3-yl]glyoxylamide Example 11N-(4-Fluorophenyl)-[1-(2-pyridylmethyl)-indol-3-yl]glyoxylamide Example12 N-4(Fluorophenyl)-[1-(3-pyridylmethyl)-indol-3-yl]glyoxylamideExample 13 N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylamideExample 14 N-(Pyridin-4-yl)-[1-(2-chlorobenzyl)-indol-3-yl]glyoxylamideExample 15 N-(Pyridin-2-yl)-[1-4-fluorobenzyl)-indol-3-yl]glyoxylamideExample 16 N-(Pyridin-4-yl)-[1-(2-pyridylmethyl)-indol-3-yl]glyoxylamideExample 17(4-Phenylpiperazin-1-yl)-[1-(4-fluoro-benzyl)indol-3-yl]glyoxylamideExample 18 N-(Pyridin-2-yl)-(1-benzylindol-3-yl)-glyoxylamide Example 19N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-6-ethoxycarbonylaminoindol-3-yl]-glyoxylamideExample 20N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-ethoxycarbonylaminoindol-3-yl]-glyoxylamideExample 21N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-6-cyclopentyloxycarbonylaminoindol-3-yl]-glyoxylamideExample 224-(Pyridin-4-yl)-piperazin-1-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamideExample 23N-(3,4,5-Trimethoxybenzyl)-N-(allyl-aminocarbonyl-2-methylprop-1-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamideExample 24N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]glyoxylamideExample 25N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]glyoxylamideExample 26N-pyridin-4-yl-[1-(4-fluorobenzyl)-5-ethoxycarbonylaminomethylindol-3-yl]-glyoxylamide

[0055] TABLE 1 Novel indolylglyoxylamides according to reaction Scheme 1Formula 1

Example R R₁ R₂ Ex. 1 H

Ex. 2 H

CH₃ Ex. 3 H

Ex. 4 H

Ex. 5 H

Ex. 6 H

Ex. 7 H

Ex. 8 H

Ex. 9 H

Ex. 10 H

Ex. 11 H

Ex. 12 H

Ex. 13 H

Ex. 14 H

Ex. 15 H

Ex. 16 H

Ex. 17 R + R₁zusam.

Ex. 18 H

Ex. 19 H

Ex. 20 H

Ex. 21 H

Ex. 22 R + R₁zusam.

Ex. 23

Ex. 24 H

Ex. 25 H

Ex. 26 H

Example R₃ R₄ Z M.p. Ex. 1 H H O 225-6° C. Ex. 2 H H O 176° C. Ex. 3 H HO 173° C. Ex. 4 H H O 140° C. Ex. 5 H H O 185° C. Ex. 6 H H O 199° C.Ex. 7 H H O >250° C. Ex. 8 H H O 149° C. Ex. 9 H H O 178-180° C. Ex. 10H H O 179° C. Ex. 11 H H O 132° C. Ex. 12 H H O 144° C. Ex. 13 H H O234° C. Ex. 14 H H O 184° C. Ex. 15 H H O 141° C. Ex. 16 H H O 202° C.Ex. 17 H H O 115° C. Ex. 18 H H O 112-3° C. Ex. 19 6-NHCOOEt H O >250°C. Ex. 20 6-NHCOOEt H O 183° C. Ex. 21

H O Olig Ex. 22 H H O 160-62° C. Ex. 23 H H O 139-141° C. Ex. 24 5-OCH₃H O 188° C. Ex. 25 5-OH H O >250° C. Ex. 26 5-CH₂—NHCOOEt H O 175-176°C.

[0056] Starting Materials for the Compounds of the General Formula 1Prepared According to Synthesis Scheme 1, which Come from Table 1

[0057] All precursors for the final synthesis stages of Examples 1 to 22and 24 to 26 are commercially available.

[0058] Furthermore, the compounds of the general formula I are alsoobtainable according to the synthesis route of Scheme 2, shown by thesynthesis of the compound Example 27:

[0059] General Procedure for the Preparation of the Compounds of theGeneral Formula 1 According to Scheme 2

[0060] 1st Stage

[0061] The indole derivative dissolved in a solvent, such as given abovefor oxalyl chloride, which can be unsubstituted or substituted on C-2 orin the phenyl ring, is added dropwise at a temperature between −5° C.and +5° C. to a solution of a simply molar up to 60% excess amount ofoxalyl chloride prepared under a nitrogen atmosphere in an aprotic ornonpolar solvent, such as, for example, in diethyl ether, methyltert-butyl ether, tetrahydrofuran, dioxane or alternativelydichloromethane. The reaction solution is then heated for 1 to 5 hoursto a temperature between 10° C. and 120° C., preferably between 20° C.and 80° C., particularly between 30° C. and 60° C., and the solvent isthen evaporated. The residue of the (indol-3-yl)glyoxylic acid chloridewhich remains is dissolved or suspended in an aprotic solvent, such as,for example, tetrahydrofuran, dioxane, diethyl ether, toluene oralternatively in a dipolar aprotic solvent, such as, for example,dimethylformamide, dimethylacetamide or dimethyl sulfoxide, cooled to atemperature between −10° C. and +10° C., preferably to −5° C. to 0° C.,and treated with a solution of the primary or secondary amine in adiluent in the presence of an acid scavenger. Possible diluents are thesolvents used for the dissolution of the “indolyl-3-glyoxylic acidchloride”. Acid scavengers used are triethylamine, pyridin,dimethylaminopyridine, basic ion exchanger, sodium carbonate, potassiumcarbonate, powdered potassium hydroxide and excess primary or secondaryamine employed for the reaction. The reaction takes place at atemperature from 0° C. to 120° C., preferably at 20-80° C., particularlybetween 40° C. and 60° C. After a reaction time of 1-4 hours andstanding at room temperature for 24 hours, the precipitate is digestedwith water, and the solid is filtered off with suction and dried invacuo. The desired compound is purified by recrystallization in anorganic solvent or by column chromatography on silica gel or alumina.The solvent used is, for example, a mixture of dichloromethane andethanol (10:1, vol/vol).

[0062] 2nd Stage

[0063] The “indol-3-ylglyoxylamide” obtained according to theabovementioned 1st Stage procedure is dissolved in a protic, dipolaraprotic or nonpolar organic solvent, such as, for example, inisopropanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide,dimethyl-acetamide, N-methylpyrrolidone, dioxane, toluene or methylenechloride and added dropwise to a suspension of a base such as, forexample, sodium hydride, powdered potassium hydroxide, potassiumtert-butoxide, dimethylaminopyridine or sodium amide in a suitablesolvent, in a molar amount or in excess prepared in a 3-necked flaskunder an N₂ atmosphere. The desired alkyl, aralkyl or heteroaralkylhalide is then added either in undiluted form or in a diluent which wasalso used, for example, to dissolve the “indol-3-yl glyoxylamide”, ifappropriate with addition of a catalyst, such as, for example, copper,and the mixture is allowed to react for some time, e.g. 30 minutes to 12hours, and the temperature is kept within a range between 0° C. and 120°C., preferably between 30° C. and 80° C., particularly between 50 and70° C. After completion of the reaction, the reaction mixture is addedto water, the solution is extracted, for example, with diethyl ether,dichloromethane, chloroform, methyl tert-butyl ether, tetrahydrofuran orN-butanol and the organic phase obtained in each case is dried usinganhydrous sodium sulfate.

[0064] The organic phase is concentrated in vacuo, the residue whichremains is crystallized by trituration or the oily residue is purifiedby distillation or by column chromatography or flash chromatography onsilica gel or alumina. The eluent used is, for example, a mixture ofmethylene chloride and diethyl ether in the ratio 8:2 (vol/vol) or amixture of methylene chloride and ethanol in the ratio 9:1 (v/v)

WORKING EXAMPLES

[0065] According to this general procedure for Stages 1 and 2, on whichsynthesis Scheme 2 is based, compounds were synthesized which havealready been prepared according to the synthesis course of reactionScheme 1 and are evident from Table 1. The relevant precursors of thesecompounds are evident from Table 2.

Example 27 N-(pyridin-4-yl)-[1-(4-flurobenzyl)indol-3-yl]-glyoxylamide

[0066] (Final substance, identical to Example 1)

[0067] 1st Stage

N-(Pyridin-4-yl)-(indol-3-yl)glyoxylamide

[0068] A solution of 10 g (85.3 mmol) of indole in 100 ml of ether isadded dropwise at 0° C. to a solution of 9 ml of oxalyl chloride in 100ml of anhydrous ether. The mixture is kept under reflux for 3 hours. Asuspension of 12 g (127.9 mmol) of 4-aminopyridine in 500 ml oftetrahydrofuran is then added dropwise at −5° C., and the reactionmixture is heated to reflux temperature with stirring for 3 hours andallowed to stand overnight at room temperature. The precipitate isfiltered and treated with water and the dried compound is purified on asilica gel column (silica gel 60, Merck AG, Darmstadt) using the eluentmethylene chloride/ethanol (10:1, v/v).

[0069] Yield: 9.8 g (43.3% of theory)

[0070] M.p.: from 250° C.

[0071] 2nd Stage

N-(Pyridin-4-yl)-[1-[4-fluorobenzylindol-3-yl]glyoxylamide

[0072] The N-(pyridin-4-yl)-(indol-3-yl)glyoxylamide obtained accordingto the 1st stage is reacted with 4-fluorobenzyl chloride according tothe “benzylation procedure” (Page 11) and the compound obtained isisolated.

[0073] Yield: 41% of theory

[0074] M.p.: 224-225° C. Elemental analysis: Calc. C 70.77 H 4.32 N11.25 Found C 70.98 H 4.40 N 11.49

Example 28 N-(4-Nitrophenyl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide(Final substance, identical to Example 7) Example 29N-(4-Fluorophenyl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide (Finalsubstance, identical to Example 6) Example 30N-)Pyridin-3-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide (Finalsubstance, identical to Example 3)

[0075] The following precursors (1st stage of reaction scheme 2, Table2) were obtained according to the present Scheme 2.

Example 31 N-(Pyridin-4-yl)-(indol-3-yl)-glyoxylamide Example 32N-(4-Nitrophenyl)-(indol-3-yl)-glyoxylamide Example 33N-(4-Fluorophenyl)-(indol-3-yl)-glyoxlyamide Example 34N-(Pyridin-3-yl)-(indol-3-yl)-glyoxylamide

[0076] TABLE 2 Novel indolylglyoxylamides according to reaction Scheme 2Formula 1

Example R R₁ R₂ R₃ R₄ Z M.p. Ex. 31 H

H H H O >250° C. Ex. 32 H

H H H O >250° C. Ex. 33 H

H H H O 233-5° C. Ex. 34 H

H H H O 235° C.

1. N-substituted indol-3-glyoxylamides of the formula

and their acid addition salts, where the radicals R, R₁, R₂, R₃, R₄ andZ have the following meaning: R=hydrogen, (C₁-C₆)-alkyl, where the alkylgroup can be mono- or polysubstituted by the phenyl ring. This phenylring, for its part, can be mono- or polysubstituted by halogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, by carboxyl groups, carboxyl groupsesterified with (C₁-C₆)-alkanols, trifluoromethyl groups, hydroxylgroups, methoxy groups, ethoxy groups, benzyloxy groups and by a benyl[sic] group which is mono- or polysubstituted in the phenyl moiety by(C₁-C₆)-alkyl groups halogen atoms or trifluoromethyl groups, R₁ can bea phenyl ring which is mono- or polysubstituted by (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, hydroxyl, benzyloxy, nitro, amino, (C₁-C₆)-alkylamino,(C₁-C₆)-alkoxy-carbonylamino and by a carboxyl group or a carboxyl groupesterified by (C₁-C₆)-alkanols, or is a pyridin structure of the formulaII

where the pyridin structure is alternatively bonded to the ring carbonatoms 2, 3 and 4 and can be substituted by the substitutents R₅ and R₆.The radicals R₅ and R₆ can be identical or different and have themeaning (C₁-C₆)-alkyl, and also the meaning (C₃-C₇)-cycloalkyl,(C₁-C₆)-alkoxy, nitro, amino, hydroxyl, halogen and trifluoromethyl andare furthermore the ethoxy-carbonylamino radical and the groupcarboxy-alkyloxy in which the alkyl group can have 1-4 C atoms, R₁ canfurthermore be a 2- or 4-pyrimidinyl-heterocycle or a pyridylmethylradical in which CH₂ can be in the 2-, 3-, 4-position where the2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group,furthermore are [sic] the 2-, 3- and 4-quinolyl structure substituted by(C₁-C₆)-alkyl, halogen, the nitro group, the amino group and the(C₁-C₆)-alkylamino radical, or are [sic] a 2-, 3- and 4-quinolyl methylgroup, where the ring carbons of the pyridylmethyl and quinolylmethylradical can be substituted by (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, nitro,amino and (C₁-C₆)-alkoxy-carbonylamino, R₁ for the case where R ishydrogen or the benzyl group, can furthermore be the acid radical of anatural or unnatural amino acid, e.g. the α-glycyl, the α-sarcosyl, theα-alanyl, the α-leucyl, the α-isoleucyl, the α-seryl, theα-phenylalanyl, the α-histidyl, the α-prolyl, the α-arginyl, theα-lysyl, the α-asparagyl and the α-glutamyl radical, where the aminogroups of the respective amino acids can be present in unprotected orprotected form and are possible protective groups for the amino functionof the carbobenzoxy radical (Z radical) and the tert-butoxycarbonylradical (BOC radical) and also the acetyl group. In the case of theasparagyl and glutamyl radical claimed for R₁, the second, nonbondedcarboxyl group is present as a free carboxyl group or in the form of anester with C₁-C₆-alkanols, e.g. as the methyl, ethyl or as thetert-butyl ester. R₁ can furthermore be theallylaminocarbonyl-2-methylprop-1-yl group. R and R₁, together with thenitrogen atom to which they are bonded, can furthermore form apiperazine ring of the formula III or a homopiperazine ring if R₁ is anaminoalkylene group in which

R₇ is an alkyl radical, a phenyl ring which can be mono- orpolysubstituted by (C₁-C₁)-alkyl, (C₁-C₆)-alkoxy, halogen, the nitrogroup, the amino function, by (C₁-C₆)-alkylamino, the benzhydryl groupand the bis-p-fluorobenzylhydryl group, R₂ can be hydrogen or the(C₁-C₆)-alkyl group, where the alkyl group can be mono- orpolysubstituted by halogen and phenyl which for its part can be mono- orpolysubstituted by halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, carboxylgroups, carboxyl groups esterified with (C₁-C₆)-alkanols,trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groupsor benzyloxy groups. The (C₁-C₆)-alkyl group counting as R₂ canfurthermore be substituted by the 2-quinolyl group and the 2-, 3- and4-pyridyl structure, which in each case can both be mono- orpolysubstituted by halogen, (C₁-C₄)-alkyl groups or (C₁-C₄)-alkoxygroups. R₂ is furthermore the aroyl radical, where the aryl moiety onwhich this radical is based is the phenyl ring which can be mono- orpolysubstituted by halogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, carboxylgroups, carboxyl groups esterified by (C₁-C₆)-alkanols, trifluoromethylgroups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxygroups, R₃ and R₄ can be identical or different and are hydrogen,hydroxyl, (C₁-C₆)-alkyl, (C₃-C₇)-cyclo-alkyl, (C₁-C₆)-alkanoyl,(C₁-C₆)-alkoxy, halogen and benzyloxy. R₃ and R₄ can furthermore be thenitro group, the amino group, the (C₁-C₄)-mono- or dialkyl-substitutedamino group, and the (C₁-C₃)-alkoxycarbonylamino function or the(C₁-C₃)-alkoxy-carbonylamino-(C₁-C₃)-alkyl function, Z is O or S, andwhere the designation alkyl, alkanol, alkoxy or alkylamino group for theradicals R, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ is normally to be understoodas meaning “straight-chain” and “branched” alkyl groups, where“straight-chain alkyl groups” can be, for example, radicals such asmethyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl and “branchedalkyl groups” designate, for example, radicals such as isopropyl ortert-butyl. “Cycloalkyl” is to be understood as meaning radicals suchas, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl, additionally the designation “halogen” represents fluorine,chlorine, bromine or iodine, and the designation “alkoxy group”represents radicals such as, for example, methoxy, ethoxy, propoxy,butoxy, isopropoxy, isobutoxy or pentoxy.
 2. Compounds according toclaim 1 N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamideN-(Pyridin-4-yl)-(4-methylindol-3-yl)glyoxylamideN-(Pyridin-3-yl)-[1-(4-fluorobenzyl)-indol-3-yl]-glyoxylamideN-(Pyridin-3-yl)-(1-benzylindol-3-yl)glyoxylamideN-(Pyridin-3-yl)-[1-(2-chorobenzyl)indol-3-yl]-glyoxylamideN-(4-Fluorophenyl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamideN-(4-Nitrophenyl)-[1-(4-fluorobenzyl)indol-3-yl]-gloxylamideN-(2-Chloropyridine-3-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamideN-(Pyridin-4-yl)-(-benzylindol-3-yl)glyoxylamideN-(Pyridin-4-yl)-[1-(3-pyridylmethyl)indol-3-yl]-glyoxylamideN-(4-Fluorophenyl)-[1-(2-pyridylmethyl)indol-3-yl]-glyoxyamideN-(4-Fluorophenyl)-[1-(3-pyridylmethyl)indol-3-yl]-glyoxylamideN-(Pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]-glyoxylamideN-(Pyridin-4-yl)-[1-(2-chlorobenzyl)indol-3-yl]-glyoxylamideN-(Pyridin-2-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamideN-(Pyridin-4-yl)-[1-(2-pyridylmethyl)indol-3-yl]-glyoxylamide(4-Phenylpiperazin-1-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamideN-(Pyridin-2-yl)-(1-benzylindol-3-yl)glyoxylamide4-(Pyridin-4-yl)-piperazin-1-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamideN-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-6-ethoxycarbonylaminoindol-3-yl]glyoxylamideN-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-ethoxycarbonylaminoindol-3-yl]glyoxylamideN-(Pyridin-4-)-[1-(4-fluorobenzyl)-6-cyclopentyloxycarbonylaminoindol-3-yl]glyoxylamideN-(3,4,5-Trimethoxybenzyl)-N-(allylaminocarbonyl-2-methylprop-1-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylamideN-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-methoxyindol-3-yl]glyoxylamideN-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-hydroxyindol-3-yl]glyoxylamideN-(Pyridin-4-yl-[1-(4-fluorobenzyl)-5-ethoxycarbonylaminomethylindol-3-yl]glyoxylamide3. Use of the compounds of the formula I according to one of claims 1and 2 for the production of a medicament.
 4. Use of the compounds of theformula I according to claims 1 to 3 on their own or in combination withone another for the production of a medicament having antiasthmatic,antiallergic and immunosuppressant/immunomodulating action fortransplantation and diseases such as, for example, psoriasis, rheumatoiddisorders and chronic polyarthritis.
 5. Medicaments comprising at leastone compound of the formula I according to one of claims 1 and 2 inaddition to customary excipients and/or diluents or auxiliaries. 6.Process for the production of a medicament, characterized in that acompound of the formula I according to one of claims 1 and 2 isprocessed with customary pharmaceutical excipients and/or diluents orother auxiliaries to give pharmaceutical preparations or brought into atherapeutically useable form.
 7. Medicaments according to claims 1 to 6in the form of tablets, coated tablets, capsules, solutions or ampoules,suppositories, patches, powder preparations which can be employed byinhalation, suspensions, creams and ointments.
 8. Process for thepreparation of N-substituted indole-3-glyoxylamides of the formula Iaccording to claims 1 and 2, in which R, R₁, R₂, R₃, R₄ and Z have themeaning mentioned in claim 1, characterized in that a) an indolederivative of the formula IV

in which R₃ and R₄ have the meaning mentioned, is added to a suspendedbase in a protic, dipolar aprotic or nonpolar organic solvent, reactedwith a reactive compound which carries the radical R₂ and where R₂ hasthe meaning mentioned, the 1-indole derivative of the formula V

in which R₂, R₃ and R₄ have the meaning mentioned, is reacted with areactive compound of the formula VI (C—Z—Hal)₂  VI in which Z has themeaning oxygen and Hal is a halogen fluorine, chlorine, bromine oriodine, and then with a primary or secondary amine of the formula VIIHNRR₁  VII in which R and R₁ have the meaning mentioned, in an aproticor dipolar aprotic solvent and the target compound of the formula I isisolated,  or b) an indole derivative of the formula IV

in which R₃ and R₄ have the meaning mentioned, is reacted in an aproticor nonpolar solvent with a reactive compound of the formula VI(C—Z—Hal)₂  VI in which Z has the meaning oxygen and Hal is a halogenfluorine, chlorine, bromine or iodine, and then in an aprotic or dipolaraprotic solvent with a primary or secondary amine of the formula VIIHNRR₁  VII in which R and R₁ have the meaning mentioned, and then the 3indole derivative of the formula VIII

in which R, R₁, R₂, R₃, R₄ and Z have the meaning mentioned, is reactedin a protic, dipolar aprotic or nonpolar organic solvent in the presenceof a suspended base with a reactive compound which carries the radicalR₂ and where R₂ has the meaning mentioned, and the target compound ofthe formula I is isolated.